National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 29, 2010 • Volume 7 / Number 13

Cancer Research Highlights

Gefitinib Improves Progression-free Survival for Metastatic Lung Cancers with EGFR Mutations

Patients newly diagnosed with metastatic non-small cell lung cancer (NSCLC) who received gefitinib (Iressa) had significantly higher response rates and longer progression-free survival compared with patients who received carboplatin plus paclitaxel (73.7 percent versus 30.7 percent and 10.8 months versus 5.4 months, respectively), according to results of a phase III trial conducted in Japan. The results were published in the June 24 New England Journal of Medicine.

All patients enrolled in the study had epidermal growth factor receptor (EGFR) mutations that were sensitive to the tyrosine kinase inhibitor (TKI) gefitinib. The patients did not have the resistant EGFR mutation T790M, and they had not been previously treated with chemotherapy.

The researchers, led by Dr. Makoto Maemondo of the Miyagi Cancer Center in Miyagi, Japan, believe that this study establishes the clinical benefit of an EGFR tyrosine kinase inhibitor as first-line therapy in patients with NSCLC and sensitive EGFR mutations.“If gefitinib is administered as second-line or third-line treatment,” he and his colleagues wrote, “patients may miss the opportunity to receive treatment because of rapidly progressive disease during or after first-line treatment.”

The trial was stopped early in 2009 after a planned interim analysis of the first 200 patients revealed a 70 percent reduction in disease progression or death in patients receiving gefitinib. Ultimately, 230 patients from 43 institutions in Japan were enrolled and analyzed. At 1 year, 42.1 percent of patients receiving gefitinib had not progressed, compared with 3.2 percent of those receiving chemotherapy; after 2 years, all chemotherapy patients had progressed, while 8.4 percent of those receiving gefitinib still had not. Women had significantly longer progression-free survival than men.

Patients who completed their first-line therapy or whose disease progressed while receiving chemotherapy were allowed to cross over and receive gefitinib, and 106 out of 112 did so. Fifty-nine percent of these patients responded to second-line therapy with gefitinib. This crossover, the researchers wrote, may have affected the overall survival difference between the two study arms, which was not statistically significant.

Gefitinib fell out of favor in the United States after a 2005 clinical trial indicated the drug had little benefit in unselected patients, and the drug currently has a very restricted label in this country, where erlotinib (Tarceva) is the approved second-line EGFR TKI of choice. Both gefitinib and erlotinib work in a similar way, and patients with sensitive EGFR mutations are also very responsive to erlotinib treatment.

Study Finds Poor Physician Adherence to Cervical Cancer Screening Guidelines

A survey of more than 1,200 primary care physicians indicates that many are not following clinical practice guidelines on recommended screening intervals for cervical cancer, both with regard to traditional Pap testing as well as a newer screening method, a DNA test for the human papillomavirus (HPV). The FDA has approved HPV DNA testing for use in conjunction with Pap testing, a process called co-testing, for women age 30 and older.

At the time the survey was conducted, guidelines from the American Cancer Society and those from the American Congress of Obstetricians and Gynecologists advised extending the interval between screenings to 3 years for low-risk women over the age of 30 after three consecutive normal Pap tests or a single normal co-test (a normal Pap test plus a negative HPV DNA test). Guidelines from the U.S. Preventive Services Task Force also are consistent with a longer interval between screening tests.

In the survey, based on a hypothetical clinical vignette of a 35-year-old, low-risk woman with three prior normal Pap tests, only 32 percent of respondents reported that they would comply with guideline recommendations, researchers from the CDC and NCI reported in the June 14 Archives of Internal Medicine. Even fewer respondents, 19 percent, would comply when, during a single visit, the low-risk woman had a normal co-test result. Approximately 60 percent of those surveyed—which included general internal medicine physicians, family practice doctors, and obstetrician-gynecologists—said they would still recommend that the woman undergo annual Pap screening.

Although the Pap test is the most commonly used cervical cancer screening method, a number of studies have shown that the DNA test for HPV—the cause of the vast majority of cervical cancer cases—is more sensitive than the Pap test in detecting high-grade precancerous lesions, spurring discussions about the optimal approach to cervical cancer screening in the United States.

This new study, however, suggests that guidelines for extending screening intervals have not influenced current clinical practice, wrote Dr. Mona Saraiya of the CDC’s Division of Cancer Prevention and Control and her colleagues. “When offered the choice for HPV testing,” they wrote, “many physicians deferred to the same pattern they used for Pap testing,” annual screening with both tests or no recommendation for HPV testing.

“These practice patterns are not likely to lead to much improvement in cervical cancer outcomes, but may result in unnecessary follow-up testing, increased risk of colposcopy-associated morbidities, and distress for patients,” said Dr. Robin Yabroff, a study co-author from NCI’s Division of Cancer Control and Population Sciences.

“New HPV infections are extremely common but overwhelmingly benign; they almost always go away by themselves,” said Dr. Mark Schiffman of NCI’s Division of Cancer Epidemiology and Genetics. “Only persistent infections are a risk factor for cancer. If you screen for HPV too often, you will detect new infections rather than persistent infections, and this poses the risk of overtreatment.”

Targeted Drug Tested in Children with Recurrent Medulloblastoma

A small phase I clinical trial testing an experimental drug that blocks the hedgehog signaling pathway has found that the drug appears safe in children with recurrent medulloblastoma, the most common malignant pediatric brain tumor. In addition, two patients whose tumors showed hedgehog pathway activation received the targeted therapy, GDC-0449, for prolonged periods, indicating to researchers that these patients likely benefited from the drug. Based on the results, presented at the annual meeting of the American Society of Clinical Oncology, the Pediatric Brain Tumor Consortium (PBTC) is planning a phase II study to verify the drug’s efficacy in children with this disease.

The hedgehog signaling pathway is important in early embryonic development and in the maintenance of adult tissues, but abnormal activation of the pathway may contribute to cancer. Approximately 20 percent of medulloblastomas are thought to involve inappropriate hedgehog signaling.

In the study, 12 of 13 children with recurrent or drug-resistant medulloblastoma tolerated the drug and did not experience the bone or dental problems observed in mice in preclinical studies. Of the two patients in the trial with confirmed activation of the hedgehog pathway in their tumors, one patient progressed after 6 months on the therapy, and the other remained on the trial without disease progression for at least 391 days, said lead investigator Dr. Amar Gajjar, representing the PBTC, which conducted the study.

The patients, all of who were between the ages of 4 and 21, received one of two different doses of the drug daily for a minimum of 28 days and continued on treatment for as long as their disease did not progress. In addition to determining the safety and proper dose of this experimental drug in children, the researchers also conducted research on pathologic and genomic methods for better identifying tumors that involve activation of the hedgehog pathway.

Although approximately 3 of 4 children diagnosed with medulloblastoma will become long-term survivors, cure is uncommon for children whose tumors recur. New, less-toxic therapies are needed for this cancer, which affects approximately 500 children in the United States each year, noted Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program. GDC-0449 is a high priority for further evaluation in patients with medulloblastoma, Dr. Smith added, especially in those whose tumors show hedgehog pathway activation.

See also: In Cancer, Hitting a Target Called Hedgehog

Vitamin D Concentrations in Blood Not Linked to Risk of Less Common Cancers

A large prospective study has found that levels of vitamin D circulating in the bloodstream are not associated with subsequent risk of developing seven rare cancers, including endometrial, esophageal, stomach, ovarian, pancreatic, and kidney cancers and non-Hodgkin lymphoma. Although each of these cancers is individually uncommon, they collectively account for about a quarter of all deaths from cancer in the United States. The results were reported in a series of studies published online in the American Journal of Epidemiology on June 18.

“These cancer sites were chosen because there was a paucity of previous epidemiological studies, though basic research and biological evidence had suggested vitamin D may play a role in altering risk for these cancers,” said Dr. Demetrius Albanes of NCI’s Division of Cancer Epidemiology and Genetics. “Because these cancers are relatively rare, no one study could address risk; by pooling data from 10 studies, we had greater power to rigorously test the vitamin D hypothesis for these cancer outcomes.” 

The researchers, part of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, measured blood concentrations of 25-hydroxy vitamin D, which is the primary form of this vitamin circulating in the bloodstream. Lower cancer risk was not observed in persons with high vitamin D blood concentrations compared with normal concentrations for any of these cancers. At the other end of the spectrum, higher cancer risk was not seen in participants with low vitamin D concentrations. However, researchers did observe an increased risk of pancreatic cancer for a small number of patients (2.3 percent) with very high blood concentrations of vitamin D (100 nmol/L or greater). “This finding needs to be followed up in further studies,” said Dr. Albanes.

Dr. Kathy J. Helzlsouer of the Prevention and Research Center at Mercy Medical Center in Baltimore, MD, who served as the chair of the project’s steering committee, wrote in the overview of the importance of optimum concentrations of vitamin D, particularly for bone health. A message of the study, she suggested, was “all things in moderation. You don’t want vitamin D levels that are too low, and you don’t want levels that are too high.”

“These studies offer compelling evidence against the hypothesis that circulating levels of vitamin D are relevant to risk of these cancers,” wrote Dr. Tim Byers of the University of Colorado Cancer Center, Aurora, in an accompanying editorial. This new information is important, he continued, because a review by the International Agency for Research on Cancer had decided that evidence was previously insufficient to draw conclusions about these cancer sites.

Cancer Survivors More Likely Than Peers to Forgo Medical Care Due to Cost

Approximately 12 million adults in the United States have a history of cancer, and this number will likely grow as the population ages. In a study led by Dr. Kathryn Weaver of Wake Forest University School of Medicine, researchers found that cancer survivors under the age of 65 were up to two times more likely to forgo or delay medical services because of cost concerns than adults without a history of cancer. These results were published online June 14 in Cancer.

The researchers used data collected between 2003 and 2006 from 6,602 cancer survivors and 104,364 adults without a history of cancer who participated in the National Health Interview Survey (NHIS); participants who only reported having nonmelanoma skin cancer were excluded. The survey collected information on age, sex, race and ethnicity, cancer site, insurance coverage, and other medical conditions besides cancer. During the interviews, the surveyors asked whether, at any time in the past 12 months, participants forwent or delayed medical care because of the cost, including prescription medications, mental healthcare, or dental care.

Overall, the prevalence of forgoing one or more medical services because of cost was 17.6 percent among cancer survivors; 7.8 percent reported forgoing medical care, 10.7 percent reported delaying medical care, 9.9 percent reported forgoing prescription medication, 11.3 percent reported forgoing dental care, and 2.7 percent reported forgoing mental health care. When the data were stratified by age, survivors 65 or older were not significantly more likely to forgo or delay care due to cost than their peers, unlike those younger than 65. Dr. Weaver believes that more uniform health insurance coverage through Medicare in those older than 65, as well as differences in the need for medical services by age, likely explain this pattern.

Extrapolating these numbers to the general population, the researchers estimated that more than 2 million cancer survivors in the United States did not get one or more medical services during the period studied, due to cost concerns. “Lack of access to medical care among cancer survivors is a significant public health concern given the importance of regular medical care for cancer survivors and their growing number,” stated the authors. More research is required, they concluded, to understand whether the medical services not received are cancer related or related to other medical conditions.

Also in the Journals: Cancer Affects Many Parents Living with Children Younger Than 18

An estimated 1.58 million U.S. cancer survivors reside with one or more children under the age of 18, according to an analysis published online June 28 in Cancer. The estimate is based on data from 13,385 adults with a history of cancer who participated in the National Health Interview Survey (NHIS) between 2000 and 2007. Dr. Kathryn Weaver, formerly of NCI’s Office of Cancer Survivorship, and her colleagues noted that 18.3 percent of recently diagnosed survivors (within the past 2 years) and 14.0 percent of all survivors were living with children younger than 18. Most of these cancer survivors are female (78.9 percent), married (69.8 percent), and under 50 years of age (85.8 percent).

The authors urged further research to assess the needs and resource referrals for this large population of families. “We hope that by documenting the significant number of families affected,” they wrote, “greater attention will be given to the identification of these potentially at-risk groups.”